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<p>Although balanced chromosomal translocations in humans are generally regarded as clinically benign, some male carriers exhibit infertility, such as azoospermia or oligozoospermia. Previous studies using mouse models have suggested that impaired sex chromosome inactivation during meiotic prophase I may contribute to infertility, but the precise mechanisms underlying variable fertility outcomes among male carriers remain unclear. In this study, we investigated male meiosis in the T6/T6 strain, a model carrying a homozygous reciprocal translocation. T6/wt males exhibited variable fertility—ranging from semi-fertile to sterile—depending on the genetic background of their mating partners. Analysis of pachytene spermatocyte spreads revealed defective synapsis of the translocation chromosomes, which frequently co-localized with the XY body. Aberrant RNA polymerase II immunofluorescence signals were observed around both the sex chromosomes and the quadrivalents, indicating failure of meiotic sex chromosome inactivation (MSCI), further supported by elongated sex chromosome morphology suggestive of heterochromatin decondensation. Notably, phase separation of the XY body appeared disrupted, likely due to the close contact with negatively charged transcripts derived from translocation chromosomes. The degree of MSCI impairment and XY body disorganization correlated with the severity of reproductive defects. These findings indicate that variable fertility among male reciprocal translocation carriers may result from differences in the degree of sex chromosome-specific phase separation during spermatogenesis, which can be perturbed by transcriptional activity from translocation chromosomes.</p>

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Impaired Phase Separation of the XY Body Underlies Spermatogenic Failure in a Translocation Carrying Mice

  • 期刊论文

  • 发表日期：

    2026年5月14日

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  • Makiko Tsutsumi,
  • Atefeh Joudaki,
  • Hiroki Kurahashi

摘要

Although balanced chromosomal translocations in humans are generally regarded as clinically benign, some male carriers exhibit infertility, such as azoospermia or oligozoospermia. Previous studies using mouse models have suggested that impaired sex chromosome inactivation during meiotic prophase I may contribute to infertility, but the precise mechanisms underlying variable fertility outcomes among male carriers remain unclear. In this study, we investigated male meiosis in the T6/T6 strain, a model carrying a homozygous reciprocal translocation. T6/wt males exhibited variable fertility—ranging from semi-fertile to sterile—depending on the genetic background of their mating partners. Analysis of pachytene spermatocyte spreads revealed defective synapsis of the translocation chromosomes, which frequently co-localized with the XY body. Aberrant RNA polymerase II immunofluorescence signals were observed around both the sex chromosomes and the quadrivalents, indicating failure of meiotic sex chromosome inactivation (MSCI), further supported by elongated sex chromosome morphology suggestive of heterochromatin decondensation. Notably, phase separation of the XY body appeared disrupted, likely due to the close contact with negatively charged transcripts derived from translocation chromosomes. The degree of MSCI impairment and XY body disorganization correlated with the severity of reproductive defects. These findings indicate that variable fertility among male reciprocal translocation carriers may result from differences in the degree of sex chromosome-specific phase separation during spermatogenesis, which can be perturbed by transcriptional activity from translocation chromosomes.